As the O2 delivery (blood flow X CaO2) to a tissue is reduced, the O2 extraction ration increases to maintain tissue metabolism. Below a critical delivery, increases in O2 extraction are inadequate to maintain O2 uptake VO2), and further decreases in delivery are associated with O2 supply-dependent VO2. At the critical point, healthy tissues typically exhibit extractions of 60-75%, whereas patients with Adult Respiratory Distress Syndrome appear to extract less than 40%. Possible mechanisms underlying the O2 supply-limitation at the critical point include (a) the extent of perfused capillary density; (b) heterogeneity of capillary or conducting vessel transit times with respect to VO2; (c) gas transport resistance introduced by plasma surrounding red cells; (d) finite rate of oxygen offloading from hemoglobin; and (e) functional shunting of O2 within tissues. A major focus of this project is to clarify the roles of perfused capillary density and microvascular transit time heterogeneity in determining the level of tissue O2 extraction at the onset of supply-dependent VO2. Specific Aim I will measure capillary recruitment and microvascular transit time heterogeneity during progressive reductions in O2 delivery produced by lowering arterial PO2 (hypoxic hypoxia) or lowering blood flow (stagnant hypoxia) in normal isolated intestine and heart. These studies will test the hypothesis that differential adjustments in perfused capillary density or transit time heterogeneity can explain the observation that a similar critical O2 delivery is reached when delivery is reduced by progressive stagnant, hypoxic, or anemic hypoxia, despite widely differing venous O2 tensions at the critical point. Specific Aim II will quantify the significance of microvascular adjustments in perfused capillary density and transit time heterogeneity for O2 exchange, by measuring the critical point during pharmacologic vasodilation and vasoconstriction in isolated intestine and heart. Additional studies will determine the significance of perfused capillary density for critical O2 extraction by reducing capillary density using graded microembolization. Perfused capillary density will be measured independently using indicator dilution methodology and quantitative morphology. Indicator dilution data will be analyzed by two independent approaches, which account for the transit time heterogeneity and the return of interstitial tracer to the capillary. Morphological analysis will use colloidal carbon to identify perfused vessels, and will quantify transit time heterogeneity using measurements of local blood flows and vascular volumes. This work will clarify and quantify the relationships among capillary surface area, microvascular flow heterogeneity, and the ability of tissues to maintain supply-independent VO2 in the face of limited O2 delivery.